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Leptin Is a Metabolic Gate for the Onset of Puberty in the Female Rat

Departments of Obstetrics & Gynecology, Box 356460 (R.A.S., D.K.C.), Physiology & Biophysics (C.C.C., J.E.T., R.A.S.), Zoology (R.A.S.), Medicine (D.S.W.), University of Washington, and Zymogenetics, Inc. (J.K.L., D.S.W.), Seattle, Washington 98195-6460 and Neuroscience Program and Department of Biology (J.E.T.), Oberlin College, Oberlin, Ohio 77074

Address all correspondence and requests for reprints to: Dr. Robert A. Steiner, Departments of Obstetrics & Gynecology, Box 356460, University of Washington, Seattle, Washington 98195-6460.

The timing of puberty onset in mammals is tightly coupled to the animal’s nutritional and metabolic state. We conducted two experiments to test the hypothesis that leptin acts as a metabolic signal for the onset of puberty. In the first experiment, we administered leptin (6.3 µg/g twice daily) to a group of normal prepubertal female rats and compared their rate of sexual maturation to that of two control groups. The group of leptin-treated animals and one group of control animals were allowed to eat ad lib, while the other group of control animals was pair-fed to the leptin-treated group. Food intake in the leptin-treated group was reduced to approximately 80% of the ad lib-fed control group, resulting in retarded growth in both leptin-treated and pair-fed animals. All measured indices of pubertal maturation—age at vaginal opening, age at first estrus, ovarian weight, ovulatory index (corpora lutea/ovarian section), uterine weight, and uterine cross-sectional area—were significantly delayed in the pair-fed group but not different between the leptin-treated group and ad lib-fed controls. The second experiment was similar to the first, except that both the leptin-treated group and the pair-fed group were fed at 70% of the ad lib-fed controls. Under these conditions, leptin only partially reversed the delay in sexual maturation, as reflected by the age at vaginal opening and first estrus. These results suggest that leptin is not the primary signal that initiates the onset of puberty but that instead, it acts in a permissive fashion, as a metabolic gate, to allow pubertal maturation to proceed—if and when metabolic resources are deemed adequate; moreover, these observations suggest that other metabolic factors, besides leptin influence the timing of puberty onset under conditions of more severe dietary stress.

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